A major factor in determining the efficacy of an intravenously-administered diagnostic or therapeutic agent is the efficiency with which the agent will be delivered to its target tissue site. For a variety of reasons, the amount of a therapeutic agent which actually penetrates the target tissue site is likely to be less than the amount of agent which was injected. Inefficient penetration of an agent into the target tissue results in the need for higher dosages of the therapeutic agent to obtain maximum therapeutic benefit at the target site, creating an increased risk of agent-induced toxicity in non-target tissues.
This problem is particularly pronounced in relation to delivery of therapeutic or diagnostic agents to malignant growths such as solid tumors. The cancerous cells of solid tumors often occupy less than half the volume of the tumor. A highly disorganized system of blood vessels weaves through the tumor mass, contributing from one to ten percent of the total tumor volume. A collagen-rich matrix known as the interstitium surrounds the cancer cells, filling the remaining space between the cells and the tumor vasculature. Plasmatic fluid can extravasate in the interstitium driven by an hydrostatic and oncotic pressure gradient. The absence of a well-defined lymphatic system in the tumor mass leads to an accumulation of these fluids in the interstitium. This accumulation leads to an increase in interstitial fluid pressure (Boucher, Y. Baxter, L. T., and Jain, R. K. (1990) Cancer Res. 50, 4478-4484). The interstitial pressure in a tumor is uniformly elevated and is approximately equal to the microvascular pressure (Boucher, Y. and Jain, R. K. (1992) Cancer Res. 52, 5110-5114). This lack of pressure differential impedes movement of a therapeutic agent into the tumor interstitium from the tumor vasculature.
One way to overcome the barrier created by the elevated pressure is to increase the difference between the microvascular pressure and interstitial pressure, either by increasing microvascular pressure or by lowering interstitial pressure. An increase of tumor microvascular pressure can be pursued by systemic infusion of vasoactive agents (Zlotecki R. A., Boucher Y., Lee I., Baxter, L. T., and Jain R. K. (1993) Cancer Res. 53, 2466-2468, and Ziotecki R. A., Baxter, L. T., Boucher Y., and Jain R. K. (1995) Microvascular Res., in press). Unfortunately, the increase in microvascular pressure is rapidly followed by a corresponding increase in interstitial pressure. The time required for the new equilibration between microvascular pressure and interstitial pressure is too short to induce any appreciable increase of macromolecular uptake, following a single or continuous injection of vasoactive agents.
A number of other efforts have been made to increase the efficiency of therapeutic agent delivery to tumors. For example, angiotensin II, a hypertension-inducing agent, has been administered at a constant dosage in combination with therapeutic agents. Other agents such as dexamethasone, indomethasin, and ketanserin have been co-administered at constant dosages with chemotherapeutic agents. In spite of these efforts, delivery of therapeutic agents to tumors remains inefficient, and further improvements are needed to optimize dosages and consequently to minimize toxicities of these agents.